Project Summary/Abstract Acute respiratory distress syndrome (ARDS) is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, kills approximately 75,000, and is seriously debilitating for many survivors29. Specific ARDS therapies do not currently exist, and efforts to reduce its burden have been limited by an incomplete characterization of the diverse molecular mechanisms underlying its pathogenesis. The cardinal, morbidity-producing feature of ARDS is non-cardiogenic pulmonary edema resulting from pulmonary vascular barrier disruption with consequent alveolar flooding, and respiratory failure. The conceptual underpinning for these events consists of cytoskeletal contraction of pulmonary endothelial cells (ECs) leading to the formation of paracellular gaps. Novel strategies which reduce the vascular permeability and lung edema of ARDS are desperately needed. The objective of this proposal is to determine the contribution of the tumor suppressor WWOX to the pathobiological processes associated with ARDS. WWOX resides at the second most active common chromosomal fragile site in the human genome, making it highly susceptible to genotoxic stress such as that which occurs during cigarette smoke and other toxic respiratory exposures. Data detailed in this application suggests that 1) loss of WWOX occurs in the lung during cigarette smoke exposure, and this event may at least partly explain an increased susceptibility for severe ARDS in smokers versus nonsmokers observed in currently emerging evidence from epidemiologic studies, and 2) WWOX exerts potent EC barrier-protective effects during both in vivo and in vitro lipopolysaccharide (LPS)-induced ARDS. This project aims to 1) determine the significance of EC WWOX expression in murine ARDS, 2) define the molecular mechanisms by which WWOX promotes EC barrier protection and 3)Establish the conceptual basis for WWOX-based therapy in cigarette-smoke primed, sepsis-induced ARDS.